The effects of blindness on the independence and productivity of afflicted individuals are profound. Although the loss of vision is the primary culprit, concomitant deficits in the regulation of non-visual photophysiology also contribute significantly to the decrease in quality of life. For example, the dysregulation of the sleep:wake cycle because of an inability to photosynchronize circadian physiology with astronomical day can have severely detrimental social consequences. Within the last 6 years, great advances have been made in identifying the retinal photoreceptor classes responsible for synchronizing circadian physiology with the light:dark cycle. Among these photoreceptors is a newly discovered class of intrinsically photosensitive retinal ganglion cell (ipRGCs) that requires the photopigment melanopsin to be sensitive to light. The visual photoreceptors (the rods and cones) also contribute to the regulation of the circadian system. The signaling mechanisms by which the visual photoreceptors and the melanopsin-containing ipRGCs convey information from the eyes to the brain are yet to be understood and are the subject of this proposal. The central hypothesis of this proposal is that ipRGCs and the classical visual photoreceptors interact to photically regulate circadian rhythms and other forms of non-visual photophysiology. The purpose of this proposal is to understand the nature of this interaction between these 2 photoreceptive systems. Our rationale is that an increased understanding of these sensory modalities and their interactions will provide phototherpeutic strategies and pharmacologic entry points to treat maladies such as recurrent insomnia in the blind and circadian-based sleep disorders.